This page summarizes R&D investment signals for DNA damage repair therapies in neurodegenerative diseases. DNA repair decline is a key feature of aging and neurodegeneration, with impaired repair mechanisms contributing to neuronal dysfunction and cell death in Alzheimer's Disease, Parkinson's Disease, and related disorders.[@dna2020]
PARP inhibitors have shown neuroprotective effects in preclinical models of Alzheimer's Disease and Parkinson's Disease by reducing DNA damage accumulation and improving mitochondrial function.[@parp2011]
Key Programs:
Eli Lilly / Mitsubishi Tanabe - Phase 2 programs in AD/PD
University research programs - Multiple Phase 1/2 trials ongoing
2. Base Excision Repair (BER)
Targets: [OGG1](/genes/ogg1), [XRCC1](/genes/xrcc1), Pol beta
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Overview
This page summarizes R&D investment signals for DNA damage repair therapies in neurodegenerative diseases. DNA repair decline is a key feature of aging and neurodegeneration, with impaired repair mechanisms contributing to neuronal dysfunction and cell death in Alzheimer's Disease, Parkinson's Disease, and related disorders.[@dna2020]
DNA damage repair in neurodegeneration spans several key mechanistic categories:
Mermaid diagram (expand to render)
Key Mechanisms
1. PARP Inhibition (Poly ADP-Ribose Polymerase)
Target: [PARP1](/genes/parp1), PARP2
PARP inhibitors have shown neuroprotective effects in preclinical models of Alzheimer's Disease and Parkinson's Disease by reducing DNA damage accumulation and improving mitochondrial function.[@parp2011]
Key Programs:
Eli Lilly / Mitsubishi Tanabe - Phase 2 programs in AD/PD
University research programs - Multiple Phase 1/2 trials ongoing
2. Base Excision Repair (BER)
Targets: [OGG1](/genes/ogg1), [XRCC1](/genes/xrcc1), Pol beta
BER is the primary pathway for repairing oxidative DNA damage, which accumulates in aging [neurons](/entities/neurons). Enhancement of BER is a promising therapeutic strategy.[@base2017]
The HR pathway is critical for repairing double-strand breaks. Dysfunction in neuronal HR contributes to genomic instability in neurodegeneration.[@homologous2018]
ATM and ATR are key DNA damage response kinases that coordinate repair, cell cycle arrest, and [apoptosis](/entities/apoptosis). Modulating these kinases may protect neurons from genotoxic stress.[@atmatr2020]
Key Programs:
ATR inhibitors - Being explored in combination therapies
| Institution | Focus Area | |---|---| | NIH (NIA, NINDS) | BER, PARP research | | University of Pennsylvania | DNA repair in AD | | Stanford University | ATM/ATR signaling | | Cambridge University | Genomic instability in neurodegeneration |
Clinical Trial Landscape
Active Recruiting Trials
Multiple Phase 1/2 trials evaluating PARP inhibitors in AD/PD
Observational studies characterizing DNA damage biomarkers
[DNA damage accumulation in neurons is a hallmark of aging and neurodegenerative diseases, DNA damage and the aging brain (2020)](https://pubmed.ncbi.nlm.nih.gov/33245678/))
[PARP inhibition in neurodegenerative disease, PARP-1 and neuroprotection (2011)](https://pubmed.ncbi.nlm.nih.gov/21450879/))
[Base excision repair in neurodegeneration, BER deficiency in Alzheimer's disease (2017)](https://pubmed.ncbi.nlm.nih.gov/28731044/))
[Homologous recombination and neuronal genome stability, BRCA1 in neuronal function (2018)](https://pubmed.ncbi.nlm.nih.gov/29506621/))
[ATM/ATR signaling in neurodegeneration, DNA damage response in Parkinson's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32406658/))
Pathway Diagram
The following diagram shows the key molecular relationships involving DNA Damage Repair Investment Landscape discovered through SciDEX knowledge graph analysis: